Renal cell carcinoma (RCC) is one of the most common malignancies with more than 30,000 new cases of renal cell carcinoma in 2014 and the incidence of this disease has increased by 2-3 folds over the last two decades. The rationale is that several studies have shown that genistein (dietary isoflavone) inhibits kidney cancer progression in various in vitro and in vivo models. However, the basic molecular mechanisms of genistein action have not been investigated in kidney cancer. In this regard, recent studies have shown that diet induces alterations in non-coding RNAs in various animal models. The main goal of this project is to investigate the basic mechanisms of genistein action through suppression of oncogenic long non-coding RNA HOTAIR that in turn modulates histone modification complexes, suppresses the epithelial-mesenchymal transition (EMT) pathway and represses kidney cancer progression using both in vitro and in vivo models. The proposed project is novel and clinically significant since such studies are lacking in kidney cancer. We hypothesis is that HOTAIR binds to the polycomb repressive complex 2 (PRC2), induces histone modification, and activates EMT pathway genes leading to kidney cancer progression and metastasis. Based on our preliminary data, kidney cancer cell lines and human kidney cancer tissues express high levels of HOTAIR and genistein inhibits HOTAIR expression. We hypothesize that genistein activated miR-141 will inhibit HOTAIR, EMT pathway genes and kidney cancer progression and metastasis. We also hypothesize that high expression of oncogenic HOTAIR and low expression of miR-141 can be used as genetic biomarkers to help predict which localized kidney cancers are likely to progress, metastasize and require aggressive clinical intervention. To test these hypotheses, we will pursue the following specific aims. Specific Aim # 1. Investigate the basic mechanisms of genistein action in inhibition of kidney cancer growth through suppression of oncogenic HOTAIR, it's binding to PRC2, activation of tumor suppressor genes and repression of EMT pathway genes using in vitro models. Specific Aim # 2. Test the hypothesis that genistein can inhibit kidney cancer growth in an immunodeficiency mouse model through suppression of oncogenic HOTAIR and it's binding to polycomb repressive complex 2 (PRC2). Specific Aim # 3. Analyze whether HOTAIR and miR-141 expression can used as genetic biomarkers to help predict which localized kidney cancers are likely to progress and metastasize. Impact: This project has high impact because it will investigate a novel and unique molecular mechanism of genistein action through suppression of oncogenic HOTAIR and its binding to PRC2 that modulates histone modification, suppression of the EMT pathway and represses kidney cancer progression. Accomplishment of this project will provide novel strategies for the management of kidney cancer.